667
VLDL into HDL (although the rate of cholesteryl ester transfer is not dependent on this process13). In vivo, cholesteryl ester transferred from HDL into VLDL will contribute to LDL, to which VLDL is converted. Although the prevention of cholesteryl ester accumulation in HDL may enhance the ability of HDL to take up more cholesterol from tissues, high rates of transfer into VLDL and thence to LDL may increase the risk of atheroma. However, cholesteryl ester retained within HDL, if it is returned directly to the liver, would not be expected to contribute to atheroma risk. Cholesteryl ester transfer protein may thus be a two-edged sword. In this context atheroma has never been successfully induced in the rat, an animal that lacks the protein.11 Furthermore, in arterial in disease14 and peripheral
hypertriglyceridaemia,15 and
hypercholesterolaemia,16
insulin-treated
diabetes,i’ all conditions atheroma, cholesteryl ester transfer
predisposing to protein activity is raised. Reduction of serum triglycerides with gemfibrozil (a lipid-lowering drug which in the Helsinki Heart Study decreased coronary heart disease mortality and morbidity18) leads to a decrease in the transfer of cholesteryl ester from HDL to VLDL.19 Cholesteryl ester transfer protein activity is also decreased by alcohol consumption,2O which may likewise be associated with decreased coronary
risk.21 Another state characterised by decreased activity of this protein is hypothyroidism,22 although here the pronounced decrease in receptor-mediated LDL catabolism1 may outweigh the benefit. Conditions in which activity is highl4-16 tend to be associated with decreased serum HDL cholesterol, whereas those in which the activity is low/8,19 including an inherited deficiency,23 show a raised HDL cholesterol. Thus, cholesteryl ester transfer protein may partly explain the apparent protective effect of high serum HDL cholesterol concentrations against coronary heart disease. 1. Durrington PN.
Hyperlipidaemia: diagnosis and management. London: Wright, 1989. 2. Myant NB. The biology of cholesterol and related steroids. London: Heinemann, 1981. 3. Miller GJ, Miller NE. Plasma-high-density-lipoprotein concentration and development of ischaemic heart disease. Lancet 1975; i: 16-19. 4. Blum CB, Levy RI, Eisenberg S, Hall M, Goebel RH, Berman M. High density lipoprotein metabolism in man. J Clin Invest 1977; 60: 795-807. 5. Loeper M, Lemaire A, Lesure A. Le pouvoir cholesterolytique du serum humain normal et pathologique. C R Soc Biol 1928; 98: 101-03. 6. Barter PJ, Jones ME. Kinetic studies of the transfer of esterified cholesterol between human low and high density lipoproteins. J Lipid Res 1980; 21: 238-49. JF, Slotte JP, Aviram M, Duell PB, Graham DL, Bierman EL. HDL receptor-mediated transport of excess cholesterol from cells. In: Miller NE, ed. HDL and atherosclerosis. Amsterdam: Elsevier, 1989: 225-32. 8. Castro GR, Fielding CJ. Early incorporation of cell-derived cholesterol into pre-&bgr;-migrating high-density lipoprotein. Biochemistry 1988; 27:
7. Oram
25-29. 9. Neary R, Bhatnagar D, Durrington PN, Ishola M, Arrol S. Mackness M. An investigation of the role of lecithin:cholesterol acyl transferase and triglyceride-rich lipoproteins in the metabolism of pre-beta high density lipoproteins. Atheroslcerosis 1991; 89: 35-48. 10. Goldberg DI, Beltz WB, Pittman RC. Evaluation of pathways for the cellular uptake of high density lipoprotein cholesterol esters in rabbits. J Clin Invest 1991; 87: 331-46.
11. Ha YC, Barter PJ. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol 1982; 71B: 265-69. 12. Pattnaik NM, Mantes A, Anglies CB, Zilversmit DB. Cholesteryl ester exchange protein in human plasma: isolation and characterisation. Biochim Biophys Acta 1978; 530: 428-38. 13. Busch SJ, Harmony JAK. Cholesteryl ester analogs inhibit cholesteryl ester but not triglyceride transfer catalyzed by the plasma cholesteryl ester-triglyceride transfer protein. Lipids 1990; 25: 216-20. 14. Ruhling K, Zane-Langhennig R, Till U, Thielmann K. Enhanced net mass transfer of HDL cholesteryl ester to apo B-containing lipoproteins in patients with peripheral vascular disease. Clin Chim Acta 1989; 184: 289-96. 15. Tall AR, Granot E, Brociar R, et al. Accelerated transfer of cholesteryl ester in dyslipidemic plasma. Role of CETP. J Clin Invest 1987; 79: 1217-25. 16. Bagdade JD, Ritter MC, Subbaiah PV. Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia. J Clin Invest
1991; 87: 1259-65.
Bagdade JD, Ritter MC, Subbaiah PV. Accelerated cholesteryl ester transfer in patients with insulin-dependent diabetes mellitus. Eur J Clin Invest 1991; 21: 161-67. 18. Frick MH, Elo O, Haapa K, Heinonen OP, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl Med J 1987; 317: 1237-45. 19. Bhatnagar D, Ishola M, Mbewu AD, Winocour PH, Mackness MI, Durrington PN. Lipoprotein composition and reverse cholesterol transport in the fasting and postprandial state in patients treated with gemfibrozil. Athersclerosis 1990; 85: 92. 20. Savolainen MJ, Hannuksela H, Seppanen S, Kervinen K, Kesaniemi
17.
YA. Increased HDL-cholesterol concentrations in alcoholics is related to low CETP activity. Eur J Clin Invest 1990; 20: 593-99. 21. Rimm EB, Giovanucci EL, Willett WC, et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 1991; 338: 464-68. 22. Dullaart RPF, Hoogenberg K, Groener JEM, Dikkeschei LD, Erkelens DW, Doorenbos H. The activity of CETP is decreased in hypothyroidism: a possible contribution to alterations in HDL. Eur J Clin Invest 1990; 20: 448-51. 23. Yamashita S, Hui DY, Wetterau JR, et al. Characterisation of plasma lipoproteins in patients heterozygous for human plasma CETP deficiency: plasma CETP regulates HDL concentrations and composition. Metabolism 1991; 40: 756-63.
Magnesium for acute myocardial infarction? Magnesium ions have several important actions in myocardium and vascular smooth muscle, including modulation of calcium and potassium channels and of adenylate cyclase activity.12 Intravenous magnesium salts have been given empirically to patients with abnormal cardiac rhythms for over 50 years, and uncontrolled studies support their
use for certain types of ventricular arrhythmia.3A wider therapeutic application for magnesium was suggested in 1986, when two randomised controlled trials showed that intravenous magnesium infused during the first 24-48 hours after suspected acute myocardial infarction reduced both mortality and the frequency of serious arrhythmias. 4,5 An overview6 of all the data available from these and subsequent controlled studies,7-10 amounting to about 1300 patients, suggests that the reduction of early arrhythmias and deaths in magnesium-treated patients is real and substantial. Mortality reduction is unlikely to be due to suppression of arrhythmias, which cause few deaths in coronary care units, so what other mechanisms might account for the results? The effects of increasing the serum magnesium
668
concentration to 2-2-5 mmol/1 are confined to the cardiovascular the most obvious system; manifestation is transient flushing. Heart rate, blood pressure, and electrophysiological variables (sinus node function, intracardiac conduction and refractory periods, and repolarisation) are little altered." Vasodilatation occurs both in the coronary circulation and in the periphery;12the overall haemodynamic response is potentially favourable in acute myocardial infarction since cardiac index is increased without a significant increase in cardiac work. Human coronary artery tone in vitro is greatly reduced by magnesium at the concentrations achieved in the clinical trials,13 and intravenous magnesium sulphate inhibits certain forms of vasospastic angina.14,15 Possible mechanisms for the vasodilatation include competition with calcium at the slow calcium channel of vascular smooth muscle2 and stimulation of prostacyclin release from endothelium.16,17 The haemodynamic effects of prostacyclin infusion on the coronary and peripheral circulations are qualitatively similar to those of infused magnesium. is Prostacyclin release by infused magnesium, with consequent inhibition of platelet adhesion and aggregation,16 may be important in view of the role of platelets in unstable coronary artery disease.19 An uncontrolled rise in intracellular calcium is a central event in myocardial cell death following ischaemia and reperfusion. ATP and creatine phosphate are rapidly depleted by uncontrolled contraction of myofibrils, and ATP synthesis is inhibited by mitochondrial calcium overload.2O Can magnesium antagonise these pathological effects of calcium? Studies in isolated perfused rat heart show that supraphysiological extracellular magnesium concentrations preserve high-energy phosphates, improve the recovery of mechanical function of the heart after reperfusion, and suppress reperfusion
arrhythmias. 1113
However,
magnesium
con-
centrations up to 15 mmol/1 were used in these experiments and it is uncertain whether the findings will apply to clinically attainable concentrations. Two clinical studies now in progress will provide further data on the use of magnesium in acute myocardial infarction. LIMIT-2 (the second Leicester Intravenous Magnesium Intervention Trial) is a single-centre placebo-controlled study of intravenous magnesium sulphate in patients with suspected acute myocardial infarction. The infusion regimen approximately doubles serum magnesium concentration for 24 hours; the concentration returns to normal at about 48 hours. The primary end-point is 28-day mortality. Recruitment of 2500 patients will be completed in 1992 and will give sufficient statistical power to detect a 35% reduction in mortality with >80% probability; the point estimate of effect suggested by the published trials is a 50% reduction. A more powerful test of the hypothesis will be provided by ISIS-4 (the fourth International Study of Infarct Survival). The ISIS researchers have adopted
as in factorial 2 x 2 x 2 design simultaneously examining the effects of oral controlled-release mononitrate and oral captopril. The aim is to recruit 30--40 000 patients over the next 2 years. Further details about ISIS-4 recruitment are given on p 689. Until the results of these trials are available it would be premature to adopt intravenous magnesium infusion in the standard management of acute myocardial infarction.
the same LIMIT-2 within a
essentially
magnesium protocol
1. White RE, Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochem Pharmacol 1989; 38: 859-67. 2. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol
Pharmacol 1987; 65: 729-45. 3. Tzivoni D, Keren A. Suppression of ventricular arrhythmias by magnesium. Am J Cardiol 1990; 65: 1397-99. 4. Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1986; i: 234-36. 5. Smith LF, Heagerty AM, Bing RF, Bamett DB. Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality. Int J Cardiol 1986; 12: 175-80. 6. Teo K, Held P, Collins R, Yusuf S. Effect of intravenous magnesium on mortality in myocardial infarction. Circulation 1990; 82: III-393. 7. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 1987; 147: 753-55. 8. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am Heart J 1989; 118: 1333-34. 9. Feldstedt M, Bouchelouche P, Svenningsen A, et al. Failing effect of magnesium substitution in acute myocardial infarction. Eur Heart J
1988; 9: 226. 10. Schechter M, Hod H, Marks N, Behar S, Kaplinsky E, Rabinowitz B. Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 1990; 66: 271-74. 11. Woods KL. Possible pharmacological actions of magnesium in acute myocardial infarction. Br J Clin Pharmacol 1991; 32: 3-10. 12. Mroczek WJ, Lee WR, Davidov ME. Effect of magnesium sulfate on cardiovascular hemodynamics. Angiology 1977; 28: 720-24. 13. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jougasaki M, Araki H. Effects of magnesium on the tone of isolated human coronary arteries. Circulation 1989; 79: 1118-24. 14. Kugiyama K, Yasue H, Okumura K, et al. Suppression of exerciseinduced angina by magnesium sulfate in patients with variant angina. JACC 1988; 12: 1177-83. 15. Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect of magnesium on anginal attack induced by hyperventilation in patients with variant angina. Circulation 1989; 79: 597-602. 16. Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in pre-eclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-78. 17. Nadler JL, Goodson S, Rude R. Evidence that prostacyclin mediates the vascular action of magnesium in humans. Hypertension 1987; 9: 379-83. 18. Firth B, Winniford MD, Campbell WB, Hillis LD. Hemodynamic effects of intravenous prostacyclin in stable angina pectoris. Am J Cardiol 1983; 52: 439-43. 19. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986; 73: 418-27. 20. Tani M. Mechanisms of Ca2+ overload in reperfused ischemic myocardium. Annu Rev Physiol 1990; 52: 543-59. 21. Borchgrevink PC, Bergan AS, Bakoy OE, Jynge P. Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR. Am J Physiol 1989; 256: H195-204. 22. Hara A, Matsumura H, Abiko Y. Beneficial effect of magnesium on the isolated perfused rat heart during reperfusion after ischaemia: comparison between pre-ischaemic and post-ischaemic administration of magnesium. Naunyn-Schmiedeberg’s Arch Pharmacol 1990; 342: 100-06. 23. Bril A, Rochette L. Prevention of reperfusion-induced ventricular arrhythmias in isolated rat heart with magnesium. Can J Physiol Pharmacol 1990; 68: 694-99.
VLDL into HDL (although the rate of cholesteryl ester transfer is not dependent on this process13). In vivo, cholesteryl ester transferred from HDL into VLDL will contribute to LDL, to which VLDL is converted. Although the prevention of cholesteryl ester accumulation in HDL may enhance the ability of HDL to take up more cholesterol from tissues, high rates of transfer into VLDL and thence to LDL may increase the risk of atheroma. However, cholesteryl ester retained within HDL, if it is returned directly to the liver, would not be expected to contribute to atheroma risk. Cholesteryl ester transfer protein may thus be a two-edged sword. In this context atheroma has never been successfully induced in the rat, an animal that lacks the protein.11 Furthermore, in arterial in disease14 and peripheral
hypertriglyceridaemia,15 and
hypercholesterolaemia,16
insulin-treated
diabetes,i’ all conditions atheroma, cholesteryl ester transfer
predisposing to protein activity is raised. Reduction of serum triglycerides with gemfibrozil (a lipid-lowering drug which in the Helsinki Heart Study decreased coronary heart disease mortality and morbidity18) leads to a decrease in the transfer of cholesteryl ester from HDL to VLDL.19 Cholesteryl ester transfer protein activity is also decreased by alcohol consumption,2O which may likewise be associated with decreased coronary
risk.21 Another state characterised by decreased activity of this protein is hypothyroidism,22 although here the pronounced decrease in receptor-mediated LDL catabolism1 may outweigh the benefit. Conditions in which activity is highl4-16 tend to be associated with decreased serum HDL cholesterol, whereas those in which the activity is low/8,19 including an inherited deficiency,23 show a raised HDL cholesterol. Thus, cholesteryl ester transfer protein may partly explain the apparent protective effect of high serum HDL cholesterol concentrations against coronary heart disease. 1. Durrington PN.
Hyperlipidaemia: diagnosis and management. London: Wright, 1989. 2. Myant NB. The biology of cholesterol and related steroids. London: Heinemann, 1981. 3. Miller GJ, Miller NE. Plasma-high-density-lipoprotein concentration and development of ischaemic heart disease. Lancet 1975; i: 16-19. 4. Blum CB, Levy RI, Eisenberg S, Hall M, Goebel RH, Berman M. High density lipoprotein metabolism in man. J Clin Invest 1977; 60: 795-807. 5. Loeper M, Lemaire A, Lesure A. Le pouvoir cholesterolytique du serum humain normal et pathologique. C R Soc Biol 1928; 98: 101-03. 6. Barter PJ, Jones ME. Kinetic studies of the transfer of esterified cholesterol between human low and high density lipoproteins. J Lipid Res 1980; 21: 238-49. JF, Slotte JP, Aviram M, Duell PB, Graham DL, Bierman EL. HDL receptor-mediated transport of excess cholesterol from cells. In: Miller NE, ed. HDL and atherosclerosis. Amsterdam: Elsevier, 1989: 225-32. 8. Castro GR, Fielding CJ. Early incorporation of cell-derived cholesterol into pre-&bgr;-migrating high-density lipoprotein. Biochemistry 1988; 27:
7. Oram
25-29. 9. Neary R, Bhatnagar D, Durrington PN, Ishola M, Arrol S. Mackness M. An investigation of the role of lecithin:cholesterol acyl transferase and triglyceride-rich lipoproteins in the metabolism of pre-beta high density lipoproteins. Atheroslcerosis 1991; 89: 35-48. 10. Goldberg DI, Beltz WB, Pittman RC. Evaluation of pathways for the cellular uptake of high density lipoprotein cholesterol esters in rabbits. J Clin Invest 1991; 87: 331-46.
11. Ha YC, Barter PJ. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol 1982; 71B: 265-69. 12. Pattnaik NM, Mantes A, Anglies CB, Zilversmit DB. Cholesteryl ester exchange protein in human plasma: isolation and characterisation. Biochim Biophys Acta 1978; 530: 428-38. 13. Busch SJ, Harmony JAK. Cholesteryl ester analogs inhibit cholesteryl ester but not triglyceride transfer catalyzed by the plasma cholesteryl ester-triglyceride transfer protein. Lipids 1990; 25: 216-20. 14. Ruhling K, Zane-Langhennig R, Till U, Thielmann K. Enhanced net mass transfer of HDL cholesteryl ester to apo B-containing lipoproteins in patients with peripheral vascular disease. Clin Chim Acta 1989; 184: 289-96. 15. Tall AR, Granot E, Brociar R, et al. Accelerated transfer of cholesteryl ester in dyslipidemic plasma. Role of CETP. J Clin Invest 1987; 79: 1217-25. 16. Bagdade JD, Ritter MC, Subbaiah PV. Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia. J Clin Invest
1991; 87: 1259-65.
Bagdade JD, Ritter MC, Subbaiah PV. Accelerated cholesteryl ester transfer in patients with insulin-dependent diabetes mellitus. Eur J Clin Invest 1991; 21: 161-67. 18. Frick MH, Elo O, Haapa K, Heinonen OP, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl Med J 1987; 317: 1237-45. 19. Bhatnagar D, Ishola M, Mbewu AD, Winocour PH, Mackness MI, Durrington PN. Lipoprotein composition and reverse cholesterol transport in the fasting and postprandial state in patients treated with gemfibrozil. Athersclerosis 1990; 85: 92. 20. Savolainen MJ, Hannuksela H, Seppanen S, Kervinen K, Kesaniemi
17.
YA. Increased HDL-cholesterol concentrations in alcoholics is related to low CETP activity. Eur J Clin Invest 1990; 20: 593-99. 21. Rimm EB, Giovanucci EL, Willett WC, et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 1991; 338: 464-68. 22. Dullaart RPF, Hoogenberg K, Groener JEM, Dikkeschei LD, Erkelens DW, Doorenbos H. The activity of CETP is decreased in hypothyroidism: a possible contribution to alterations in HDL. Eur J Clin Invest 1990; 20: 448-51. 23. Yamashita S, Hui DY, Wetterau JR, et al. Characterisation of plasma lipoproteins in patients heterozygous for human plasma CETP deficiency: plasma CETP regulates HDL concentrations and composition. Metabolism 1991; 40: 756-63.
Magnesium for acute myocardial infarction? Magnesium ions have several important actions in myocardium and vascular smooth muscle, including modulation of calcium and potassium channels and of adenylate cyclase activity.12 Intravenous magnesium salts have been given empirically to patients with abnormal cardiac rhythms for over 50 years, and uncontrolled studies support their
use for certain types of ventricular arrhythmia.3A wider therapeutic application for magnesium was suggested in 1986, when two randomised controlled trials showed that intravenous magnesium infused during the first 24-48 hours after suspected acute myocardial infarction reduced both mortality and the frequency of serious arrhythmias. 4,5 An overview6 of all the data available from these and subsequent controlled studies,7-10 amounting to about 1300 patients, suggests that the reduction of early arrhythmias and deaths in magnesium-treated patients is real and substantial. Mortality reduction is unlikely to be due to suppression of arrhythmias, which cause few deaths in coronary care units, so what other mechanisms might account for the results? The effects of increasing the serum magnesium
668
concentration to 2-2-5 mmol/1 are confined to the cardiovascular the most obvious system; manifestation is transient flushing. Heart rate, blood pressure, and electrophysiological variables (sinus node function, intracardiac conduction and refractory periods, and repolarisation) are little altered." Vasodilatation occurs both in the coronary circulation and in the periphery;12the overall haemodynamic response is potentially favourable in acute myocardial infarction since cardiac index is increased without a significant increase in cardiac work. Human coronary artery tone in vitro is greatly reduced by magnesium at the concentrations achieved in the clinical trials,13 and intravenous magnesium sulphate inhibits certain forms of vasospastic angina.14,15 Possible mechanisms for the vasodilatation include competition with calcium at the slow calcium channel of vascular smooth muscle2 and stimulation of prostacyclin release from endothelium.16,17 The haemodynamic effects of prostacyclin infusion on the coronary and peripheral circulations are qualitatively similar to those of infused magnesium. is Prostacyclin release by infused magnesium, with consequent inhibition of platelet adhesion and aggregation,16 may be important in view of the role of platelets in unstable coronary artery disease.19 An uncontrolled rise in intracellular calcium is a central event in myocardial cell death following ischaemia and reperfusion. ATP and creatine phosphate are rapidly depleted by uncontrolled contraction of myofibrils, and ATP synthesis is inhibited by mitochondrial calcium overload.2O Can magnesium antagonise these pathological effects of calcium? Studies in isolated perfused rat heart show that supraphysiological extracellular magnesium concentrations preserve high-energy phosphates, improve the recovery of mechanical function of the heart after reperfusion, and suppress reperfusion
arrhythmias. 1113
However,
magnesium
con-
centrations up to 15 mmol/1 were used in these experiments and it is uncertain whether the findings will apply to clinically attainable concentrations. Two clinical studies now in progress will provide further data on the use of magnesium in acute myocardial infarction. LIMIT-2 (the second Leicester Intravenous Magnesium Intervention Trial) is a single-centre placebo-controlled study of intravenous magnesium sulphate in patients with suspected acute myocardial infarction. The infusion regimen approximately doubles serum magnesium concentration for 24 hours; the concentration returns to normal at about 48 hours. The primary end-point is 28-day mortality. Recruitment of 2500 patients will be completed in 1992 and will give sufficient statistical power to detect a 35% reduction in mortality with >80% probability; the point estimate of effect suggested by the published trials is a 50% reduction. A more powerful test of the hypothesis will be provided by ISIS-4 (the fourth International Study of Infarct Survival). The ISIS researchers have adopted
as in factorial 2 x 2 x 2 design simultaneously examining the effects of oral controlled-release mononitrate and oral captopril. The aim is to recruit 30--40 000 patients over the next 2 years. Further details about ISIS-4 recruitment are given on p 689. Until the results of these trials are available it would be premature to adopt intravenous magnesium infusion in the standard management of acute myocardial infarction.
the same LIMIT-2 within a
essentially
magnesium protocol
1. White RE, Hartzell HC. Magnesium ions in cardiac function. Regulator of ion channels and second messengers. Biochem Pharmacol 1989; 38: 859-67. 2. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol
Pharmacol 1987; 65: 729-45. 3. Tzivoni D, Keren A. Suppression of ventricular arrhythmias by magnesium. Am J Cardiol 1990; 65: 1397-99. 4. Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1986; i: 234-36. 5. Smith LF, Heagerty AM, Bing RF, Bamett DB. Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality. Int J Cardiol 1986; 12: 175-80. 6. Teo K, Held P, Collins R, Yusuf S. Effect of intravenous magnesium on mortality in myocardial infarction. Circulation 1990; 82: III-393. 7. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med 1987; 147: 753-55. 8. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am Heart J 1989; 118: 1333-34. 9. Feldstedt M, Bouchelouche P, Svenningsen A, et al. Failing effect of magnesium substitution in acute myocardial infarction. Eur Heart J
1988; 9: 226. 10. Schechter M, Hod H, Marks N, Behar S, Kaplinsky E, Rabinowitz B. Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 1990; 66: 271-74. 11. Woods KL. Possible pharmacological actions of magnesium in acute myocardial infarction. Br J Clin Pharmacol 1991; 32: 3-10. 12. Mroczek WJ, Lee WR, Davidov ME. Effect of magnesium sulfate on cardiovascular hemodynamics. Angiology 1977; 28: 720-24. 13. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jougasaki M, Araki H. Effects of magnesium on the tone of isolated human coronary arteries. Circulation 1989; 79: 1118-24. 14. Kugiyama K, Yasue H, Okumura K, et al. Suppression of exerciseinduced angina by magnesium sulfate in patients with variant angina. JACC 1988; 12: 1177-83. 15. Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect of magnesium on anginal attack induced by hyperventilation in patients with variant angina. Circulation 1989; 79: 597-602. 16. Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in pre-eclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-78. 17. Nadler JL, Goodson S, Rude R. Evidence that prostacyclin mediates the vascular action of magnesium in humans. Hypertension 1987; 9: 379-83. 18. Firth B, Winniford MD, Campbell WB, Hillis LD. Hemodynamic effects of intravenous prostacyclin in stable angina pectoris. Am J Cardiol 1983; 52: 439-43. 19. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986; 73: 418-27. 20. Tani M. Mechanisms of Ca2+ overload in reperfused ischemic myocardium. Annu Rev Physiol 1990; 52: 543-59. 21. Borchgrevink PC, Bergan AS, Bakoy OE, Jynge P. Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR. Am J Physiol 1989; 256: H195-204. 22. Hara A, Matsumura H, Abiko Y. Beneficial effect of magnesium on the isolated perfused rat heart during reperfusion after ischaemia: comparison between pre-ischaemic and post-ischaemic administration of magnesium. Naunyn-Schmiedeberg’s Arch Pharmacol 1990; 342: 100-06. 23. Bril A, Rochette L. Prevention of reperfusion-induced ventricular arrhythmias in isolated rat heart with magnesium. Can J Physiol Pharmacol 1990; 68: 694-99.
